When a new drug enters the market, it generally causes a reawakening of issues that are understood but often not well appreciated. Such is the case of adding Pradaxa to warfarin as a drug available for the treatment of stroke prevention in atrial fibrillation.
One would think that after 60 years, we would have a better handle on the bleeding events that these drugs cause, but it seems that we get further and further from the mark. I have reviewed some of this information in the past, and I urge those of you who have not read about this topic before to check out those blogs.
Some of the reasons we have more problems with bleeding and anticoagulants now is that we care for sicker patients, and patients are older. These two factors combined are a recipe for trouble.
In the past, warfarin was used primarily by itself. Now, warfarin is often combined with aspirin and often, Plavix in what is known as “triple therapy.” This is necessary because aspirin and Plavix care for the stent, and warfarin cares for the embolic phenomenon of atrial fibrillation. Unfortunately, they don’t do both.
We have several scores to help us decide which patients may be at risk and which are not. Importantly, however, an individual is 100% of their own risk. 100 individuals have a risk of 1-2%, but for that 1 or 2 patients, the risk is 50-50. These scores include CHA2DS2-VAS2, which is an improved CHADS2 score, and tell us what the risk is for an individual patient and the HAS-BLED score, which tells us what the risk of bleeding is for that patient.
All this comes to the forefront again as the FDA has launched a well-publicized review of the bleeding risk of Pradaxa. Several European countries and Australia have already issued warnings about Pradaxa and bleeding.
In November, the manufacturer released data that, since released worldwide, there have been 260 fatal bleeding events with Pradaxa. One of the challenges that doctors face on both sides of the treatment equation is translating real world use of a drug and its use in a randomized clinical trial, which is tightly controlled. In the study used for FDA approval known as RE-LY, the fatal bleeding rate was 0.23% or 230 per 100,000 patient years. Warfarin was 0.33% or 330 per 100,000 patient years in that trial.
Is this the rate we are seeing now, or is it higher? Last week I blogged about the huge problem of anticoagulants, mostly warfarin, in hospital admissions because of bleeding issues. This review by the FDA is just an extension of this. According to Boehringer Ingelheim, the manufacturer of Pradaxa, their data shows that the 260 fatal bleeds is spread across 410,000 patient years, which makes the rate 63 events per 100,000 patient years and is well below that of the RE-LY trial.
What we really need to know is the rate of fatal bleeding with warfarin compared to that of Pradaxa in the “real world." This is difficult to accomplish because often the cause of death is not coded properly. The intracranial bleed that was admitted on warfarin with an “in range” INR. Is that an event or not?
It is clear that what is wrong is our inadequate monitoring of after market drug use and problems. I have stated in the past that less evaluation is needed upfront, and more evaluation is needed after a drug or device is released. This post marketing needs to be built into the drug or device release and not an afterthought. This is the type of follow-up that is being put into place with the release of the TAVI valves that I have blogged about in the past.
Stay tuned...we have not heard the last of this topic.